Abuse-deterrent drug formulations

ABSTRACT

An abuse-deterrent pharmaceutical composition has been developed to reduce the likelihood of improper administration of drugs, especially drugs such as opiods. In the preferred embodiment, the drug is modified to increase its lipophilicity by forming a salt between the drug and one or more fatty acids wherein the concentration of the one or more fatty acids is one to 15 times the molar amount of the active agent, preferably two to ten times the molar amount of the active agent. In one embodiment the modified drug is homogeneously dispersed within microparticles composed of a material that is either slowly soluble or not soluble in water. In some embodiments the drug containing microparticles or drug particles are coated with one or more coating layers, where at least one coating is water insoluble and preferably organic solvent insoluble. The abuse-deterrent composition prevents the immediate release of a substantial portion of drug, even if the physical integrity of the formulation is compromised (for example, by chopping with a blade or crushing) and the resulting material is placed in water, snorted, or swallowed. However, when administered as directed, the drug is slowly released from the composition as the composition is broken down or dissolved gradually within the GI tract by a combination of enzymatic degradation, surfactant action of bile acids, and mechanical erosion.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of prior application U.S. Ser. No.13/870,690 filed Apr. 25, 2013, entitled “Abuse-Deterrent DrugFormulations” by Jane Hirsh, Alison B. Fleming, Roman V. Rariy, andAlexander M. Klibanov, which is a continuation of prior U.S. Ser. No.12/823,628 filed Jun. 25, 2010, entitled “Abuse-Deterrent DrugFormulations” by Jane Hirsh, Alison Fleming, Roman V. Rariy, andAlexander M, Klibanov, now U.S. Pat. No. 8,449,909, which is acontinuation of prior application U.S. Ser. No. 11/149,867 filed Jun.10, 2005, entitled “Abuse-Deterrent Drug Formulations” by Jane Hirsh,Alison B. Fleming, Roman V, Rariy, and Alexander M. Klibanov, now U.S.Pat. No. 7,771,707 and claims priority under 35 U.S.C. §119 to U.S.Provisional Patent Application No. 60/579,191 filed Jun. 12, 2004entitled “Abuse-Deterrent Drug Formulations,” all of which are herebyincorporated by reference in their entireties and for all purposes.

FIELD OF THE INVENTION

The present invention is generally in the field of pharmaceuticalcompositions, specifically compositions designed to reduce the potentialfor improper administration of drugs that are subject to abuse.

BACKGROUND OF THE INVENTION

Oxycodone, morphine, and other opioid analgesics are therapeuticallyuseful and effective medications, e.g., as pain killers, whenadministered orally. Unfortunately, they also pose a severe threat forwillful abuse due to their ability to alter mood and/or cause a sense ofeuphoria. Currently available sustained release formulations of suchdrugs, which contain a relatively large amount of drug intended to bereleased from the formulation over an extended period of time, areparticularly attractive to abusers since the sustained release coatingcan be destroyed by crushing or grinding the formulation. The crushedmaterial no longer controls the release of drug. Depending on the drug,abusers can then (1) snort the material, (2) swallow the material or (3)dissolve the material in water and subsequently inject it intravenously.The dose of drug contained in the formulation is thus absorbedimmediately through the nasal or GI mucosa (for snorting or swallowing,respectively) or is administered systemically in a bolus via thecirculatory system (for IV injection). These abuse methods result in therapid bioavailability of relatively high doses of drug, giving theabuser a “high”. Since relatively simple methods (crushing, grinding,chewing and/or dissolution in water) can be used to transform suchformulations into an abusable form, they provide virtually no deterrentto a potential abuser.

For example, the FDA recently strengthened the warnings and precautionssections in the labeling of OxyContin® (oxycodone HClcontrolled-release) tablets, a narcotic drug approved for the treatmentof moderate to severe pain, because of continuing reports of abuse anddiversion. OxyContin®, contains oxycodone HCl (available in 10, 20, 40and 80 mg strengths), an opioid agonist with an addiction potentialsimilar to that of morphine. Opioid agonists are substances that act byattaching to specific proteins called opioid receptors, which are foundin the brain, spinal cord, and gastrointestinal tract. When these drugsattach to certain opioid receptors in the brain and spinal cord they caneffectively block the transmission of pain messages to the brain.OxyContin® is supplied in a controlled-release dosage form and isintended to provide up to 12 hours of relief from moderate to severepain. The warning specifically states that the tablet must be takenwhole and only by mouth. When the tablet is chewed or crushed and itscontents are swallowed, snorted into the nostrils or dissolved andsubsequently injected intravenously, the controlled release mechanism isdestroyed and a potentially lethal dose of oxycodone becomesbioavailable.

In recent years, there have been numerous reports of Oxycodone diversionand abuse in several states. For example, DEA's Office of DiversionControl reported 700 OxyContin® thefts in the U.S. between January 2000and June 2001. Some of these reported cases have been associated withserious consequences including death.

Oxycodone is a controlled substance in Schedule II of the ControlledSubstances Act (CSA), which is administered by the Drug EnforcementAdministration (DEA). Despite the fact that Schedule II provides themaximum amount of control possible under the CSA for approved drugproducts, in practice, it is difficult for law enforcement agencies tocontrol the diversion or misuse of legitimate prescriptions. Althoughabuse, misuse, and diversion are potential problems for all opioids,including Oxycodone, opioids are a very important part of the medicalarsenal for the management of pain when used appropriately under thecareful supervision of a physician.

Currently available formulations for such drugs are designed for oraladministration but do not include mechanisms to prevent or retardimproper methods of administration such as chewing, injection andsnorting. This represents a serious problem given the large number oflegitimate prescriptions written in the U.S.; for example, the medicaluse of opioids within the U.S. increased 400% from 1996 to 2000. Theproblems with abuse are significant and longstanding, and efforts todesign new abuse-resistant or abuse-deterrent formulations have beenlargely unsuccessful. U.S. Pat. Nos. 3,980,766, 4,070,494 and 6,309,668describe formulations designed to prevent the injection of compositionsmeant for oral administration. U.S. Pat. No. 3,980,766 describes theincorporation of an ingestible solid which causes a rapid increase inviscosity upon concentration of an aqueous solution thereof. U.S. Pat.No. 4,070,494 describes the incorporation of a non-toxic, water gelablematerial in an amount sufficient to render the drug resistant to aqueousextraction. U.S. Pat. No. 6,309,668 describes a tablet for oraladministration containing two or more layers comprising one or moredrugs and one or more gelling agents within separate layers of thetablet. The resulting tablet forms a gel when combined with the volumeof water necessary to dissolve the drug; this formulation thus reducesthe extractability of the drug from the tablet. It should be noted thatalthough these compositions preclude abuse by injection, this approachfails to prevent abuse by crushing and swallowing or snorting theformulation, which are commonly reported methods of abuse associatedwith OxyContin®.

U.S. Pat. Nos. 3,773,955 and 3,966,940 describe formulations containinga combination of opioid agonists and antagonists, in which theantagonist does not block the therapeutic effect when the admixture isadministered orally, but which does not produce analgesia, euphoria orphysical dependence when administered parenterally by an abuser. U.S.Pat. No. 4,457,933 describes a method for decreasing both the oral andparenteral abuse potential of strong analgesic agents by combining ananalgesic dose of the analgesic agent with an antagonist in specific,relatively narrow ratios. U.S. Pat. Nos. 6,277,384, 6,375,957 and6,475,494 describe oral dosage forms including a combination of anorally active opioid agonist and an orally active opioid antagonist in aratio that, when delivered orally, is analgesically effective but thatis aversive in a physically dependent subject. While such a formulationmay be successful in deterring abuse, it also has the potential toproduce adverse effects in legitimate patients.

It is therefore an object of the present invention to provide apharmaceutical composition that significantly reduces the potential forimproper administration or use of drugs but which, when administered asdirected, is capable of delivering a therapeutically effective dose.

BRIEF SUMMARY OF THE INVENTION

An abuse-deterrent pharmaceutical composition has been developed toreduce the likelihood of improper administration of drugs, especiallydrugs such as opioids. In the preferred embodiment, the drug is modifiedto increase its lipophilicity by forming a salt between the drug and oneor more fatty acids or amines, wherein the concentration of the one ormore fatty acids or amines is one to fifteen times the molar amount ofthe active agent, preferably two to ten times the molar amount of theactive agent. In one embodiment the modified drug is homogeneouslydispersed within microparticles composed of a material that is eitherslowly soluble or insoluble in water. In some embodiments the drugcontaining microparticles or drug particles are coated with one or morecoating layers. The abuse-deterrent composition prevents the immediaterelease of a substantial portion of drug, even if the physical integrityof the formulation is compromised (for example, by chopping with a bladeor crushing) and the resulting material is placed in water, snorted, orswallowed. However, when administered as directed, the drug is slowlyreleased from the composition as the composition is broken down ordissolved gradually within the GI tract by a combination of enzymaticdegradation, surfactant action of bile acids, and mechanical erosion.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of the testing procedures for determiningabuse resistance of the formulations.

FIG. 2 is a graph showing the percentage of oxycodone released in OralAbuse Testing as a function of composition.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

“Composition” as used herein refers to the drug dosage unit foradministration to a patient. It may also be used in reference solely tothe active ingredient, or to the formulation containing the activeingredient.

“Abuse-deterrent composition” or “abuse-deterrent formulation” are usedinterchangeably herein to refer to compositions that reduce thepotential for improper administration of drugs but that deliver atherapeutically effective dose when administered as directed. Improperadministration includes tampering with the dosage form and/oradministering the drug by any route other than instructed.

“Drug”, “active agent”, and “pharmacologically active agent” are usedinterchangeably herein to refer to a chemical compound that induces adesired pharmacological and/or physiological effect. The terms alsoencompass pharmaceutically acceptable derivatives of those active agentsspecifically mentioned herein, including, but not limited to, salts,solvates, hydrates, complexes with one or more molecules, prodrugs,active metabolites, lipophilic derivatives, analogs, and the like.

“Lipophilic derivative” and “lipophilic drug derivative”, as usedherein, refer to derivatives of the drug that are less soluble in waterthan the most soluble salt of the drug. The most soluble salt isselected from either alkaline metal salts (for acidic drugs) or acidaddition salts of (for basic drugs).

“Microparticle” as used herein refers to a composition comprising a drugdispersed within a carrier material. “Coated microparticle” as usedherein refers to a composition comprising a drug containingmicroparticle or a drug particle coated with one or more coating layers.Microparticles and coated microparticles have a size range of 10 to 3000microns in diameter.

II. Compositions

The currently available sustained release dosage forms containingnarcotic analgesics and other drugs are subject to misuse, in part,because mechanical destruction of the dosage form exposes theencapsulated drag and allows for immediate dissolution of the drug intoaqueous media. Two properties of the dosage form that contribute to thisoutcome are (1) the ease with which drug is exposed to the extractionmedia and (2) the high water solubility of the drug salt form.

In the composition disclosed herein, one or both of these properties arealtered in order to achieve an abuse-deterrent composition.Specifically, in the preferred embodiment, the drug is modified toincrease its lipophilicity and, in additional preferred embodiments, isthen homogeneously dispersed within a material that is either slowlysoluble or not soluble in water and subsequently formulated intomicroparticles. The drug may be present in the form of discreteparticles or may be partially or fully dispersed in the carrier materialon a molecular level.

The abuse deterrent composition preferably comprises a drug modified toincrease its lipophilicity. In other preferred embodiments, the drug ishomogenously dispersed within microparticles composed of a material thatis either slowly soluble in water or water insoluble. The compositionsslow the release of drug if the dosage form is chopped or crushed andthe resulting material is placed in water, snorted, or swallowed sincemost of the drug will remain associated with or entrapped withinportions of the core material of the microparticles. In some embodimentsthe drug containing microparticles or individual drug particles arecoated with one or more coating layers, where at least one coating iswater insoluble and preferably organic solvent insoluble, butenzymatically degradable. The components of the resulting coatedmicroparticles are not mutually soluble in water, organic solvents, orany combination thereof, such that no one solvent or enzyme solution iscapable of dissolving the formulation in its entirety in vitro. Itfollows that extraction of the drug from the formulation cannot becarried out in one step. However, when administered as directed, thedrug is slowly released from the formulation since it is eroded withinthe environment of the gastrointestinal tract.

A. Drugs to be Formulated

There are many drugs that it is desirable to deliver using thecompositions described herein. The Controlled Substances Act (CSA),Title II of the Comprehensive Drug Abuse Prevention and Control Act of1970, places all substances that are regulated under existing federallaw into one of five schedules based upon the substance's medicinalvalue, harmfulness, and potential for abuse or addiction. Drugs that arepreferred include those classified as Schedule II, III, IV and V drugs.Drugs that are most preferable include those, like oxycodone, that arecurrently formulated as sustained or controlled release compositions,where drug release is intended to occur over a prolonged period of timethrough the gastrointestinal tract, and immediate or burst release, forexample, by inhalation or injection, is undesirable. As used herein,drugs prone to abuse refer to controlled substance specified as scheduleII, II, IV and V drugs.

The terms “drug”, “active agent”, and “pharmacologically active agent”are used interchangeably herein to refer to a chemical compound thatinduces a desired pharmacological, physiological effect. The terms alsoencompass pharmaceutically acceptable derivatives of those active agentsspecifically mentioned herein, including, but not limited to, salts,solvates, hydrates, complexes with one or more molecules, prodrugs,active metabolites, lipophilic derivatives, analogs, and the like. Whenthe terms “active agent”, “pharmacologically active agent” and “drug”are used, or when a particular drug, such as oxycodone, is identified,it is to be understood as including the active agent per se as well aspharmaceutically acceptable salts, solvates, hydrates, complexes withone or more molecules, prodrugs, active metabolites, and lipophilicderivatives and analogs.

Examples of preferred drugs include, 1-phenylcyclohexylamine,1-piperidinocyclohexanecarbonitrile, alfentanil, alphacetylmetbadol,alphaprodine, aiprazolam, amobarbital, amphetamine, anileridine,apomorphine, aprobarbital, barbital, barbituric acid derivative,bemidone, benzoylecgonine, benzphetamine, betacetylmethadol,betaprodine, bezitramide, bromazepam, buprenorphine, butabarbital,butalbital, butorphanol, camazepam, cathine, chloral, chlordiazepoxide,clobazam, clonazepam, clorazepate, clotiazepam, cloxazolam, cocaine,codeine, chlorphentermine, delorazepam, dexfenfluramine, dextromoramide,dextropropoxyphen, dezocine, diazepam, diethylpropion, difenoxin,dihydrocodeine, dihydromorphine, dioxaphentyl butyrate, dipanone,diphenoxylate, diprenorphine, ecgonine, enadoline, eptazocine,estazolam, ethobeptazine, ethyl loflazepate, ethylmorphine, eorphine,femproponex, fencamfamin, fenfluramine, fentanyl, fludiazepam,flunitrazepam, flurazepam, glutethimide, halazepam, haloxazolam,huxalgon, hydrocodone, hydromorphone, isomethadone, hydrocodone,ketamine, ketazolam, ketobemidone, levanone, levoalphacetylmethadol,levomethadone, levomethadyl acetate, levomethorphan, levorphanol,lofentanil, loperamide, loprazolam, lorazepam, lormetazepam, lysergicacid, lysergic acid amide, mazindol, medazepam, mefenorex, meperidine,meptazinol, metarocine, methadone, methamphetamine, methohexital,methotrimeprazine, methyldihydromorphinone, methylphenidate,methylphenobarbital, metopon, morphine, nabilone, nalbuphine, nalbupine,nalorphine, narceine, nefopam, nicomorphine, nimetazepam, nitrazepam,nordiazepam, normethadone, normorphine, oxazeparm, oxazolam, oxycodone,oxymorphone, pentazocine, pentobarbital, phenadoxone, phenazocine,phencyclidine, phendimetrazine, phenmetrazine, pheneridine, piminodine,prodilidine, properidine, propoxyphene, racemethorphan, racemorphan,racemoramide, remifentanil, secobarbital, sufentanil, talbutal,thebaine, thiamylal, thiopental, tramadol, trimeperidine, andvinbarbital.

In addition to the compounds above, the following scheduled drugs may beincorporated into the composition: allobarbitone, alprazolam,amylobarbitone, aprobarbital, barbital, barbitone, benzphetamine,brallobarbital, bromazepam, brotizolam, buspirone, butalbital,butobarbitone, butorphanol, camazepam, captodiame, carbromal,carfentanil, carpipramine, cathine, chloral, chloral betaine, chloralhydrate, chloralose, chlordiazepoxide, chlorhexadol, chlormethiazoleedisylate, chlormezanone, cinolazepam, clobazam, potassium clorazepate,clotiazepam, cloxazolam, cyclobarbitone, delorazepam, dexfenfluramine,diazepam, diethylpropion, difebarbamate, difenoxin, enciprazine,estazolam, ethyl loflazepate, etizolam, febarbamate, fencamfamin,fenfluramine, fenproporex, fluanisone, fludiazepam, flunitraam,flunitrazepam, flurazepam, flutoprazepam, gepirone, glutethimide,halazepam, haloxazolam, hexobarbitone, ibomal, ipsapirone, ketazolam,loprazolam mesylate, lorazepam, lormetazepam, mazindol, mebutamate,medazepam, mefenorex, mephobarbital, meprobamate, metaclazepam,methaqualone, methohexital, methylpentynol, methylphenobarbital,midazolam, milazolam, morphine, nimetazepam, nitrazepam, nordiazepam,oxazepam, oxazolam, paraldehyde, pemoline, pentabarbitone, pentazocine,pentobarbital, phencyclidine, phenobarbital, phendimetrazine,phenmetrazine, phenprobamate, phentermine, phenyacetone, pinazepam,pipradol, prazepam, proxibarbal, quazepam, quinalbaritone, secobarbital,secbutobarbitone, sibutramine, temazepam, azepan, tetrazepam, triazolam,triclofos, zalepan, zaleplon, zolazepam, zolpidem, and zopiclone. In apreferred embodiment, the pharmaceutically active agent is oxycodone.Certain compounds described herein may exist in particular geometric orstereoisomeric forms. The compositions disclosed herein contemplate allsuch compounds, including cis- and trans-isomers, R- and S-enantiomers,diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof,compounds of different spatial conformations, and other mixtures thereofAdditional asymmetric carbon atoms may be present in a substituent suchas an alkyl group.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the compounds can besynthesized from the parent compound, which contains a basic or acidicmoiety, by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 20th ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000, p. 704, the disclosure of which is herebyincorporated by reference.

Optionally, the composition described herein can further include a drughaving no appreciable abuse potential.

In preferred embodiments, the solubility characteristics of a drug arealtered prior to incorporation into the formulation. Modification of thedrug to produce a more lipophilic derivative serves to reduce the watersolubility of the drug and thus reduces the aqueous extractability.Furthermore, if the drug is made more lipophilic, it can be solubilizedin a fatty substance or wax like mixture, rather than physicallydispersed in a particulate form. Solubilization of drug enhances theabuse-deterrent properties of microparticles formulated from the mixtureas it is difficult to extract drug from an intimately dispersedcomposition.

Some of the methods that can be used to alter the drug's lipophilicityare outlined below. It is understood that two or more approaches can becombined to achieve a desired solubility profile.

B. Lipophilic Drug Formulations

In one embodiment, drug is made more lipophilic by eliminating orreducing the overall charge of the drug molecule. For example, for abasic drug, a water soluble salt (such as hydrochloride, sulfate, ormaleate) can be converted to a free base using techniques known in theart. Correspondingly, in the case of an acidic drug, a water solublesalt (such sodium, potassium, or the like) can be converted to a freeacid.

In another embodiment, the drug's lipophilicity is increased by forminga salt between a drug molecule and one or more charged lipophiliccompounds. In this case the lipophilicity of the resulting salt can bemanipulated by varying the lipophilicity of the counter-ion. In generallipophilic (fatty) acids or amines with chain lengths between C₅-C₃₀ aresuitable lipophilic counter-ion candidates. Suitable (fatty) acids andamines include, but are not limited to, pentanoic acid, hexanoic(caproic) acid, heptanoic acid, octanoic (caprylic) acid, nonanoic acid,decanoic (capric) acid, undecanoic acid, dodecanoic (lauric) acid,tridecanoic acid, tetradecanoic (myristic) acid, pentadecanoic acid,hexadecanoic (palmitic) acid, heptadecanoic (margaric) acid,octadecanoic (stearic) acid, nonadecanoic acid, cicosanoic (arachidic)acid, heneicosanoic acid, docosanoic (behenic) acid, tricosanoic acid,tetracosanoic (lignoceric) acid, pentacosanoic acid, hexacosanoic acid,heptacosanoic acid, octacosanoic acid, nonacosanoic acid, triacontanoicacid, linoleic acid, oleic acid, octyl amine, lauryl amine, stearylamine, palmityl amine, linoleyl amine, and oleyl amine and mixturesthereof. In a preferred embodiment, the fatty acid is myristic acid or amixture of stearic and palmitic acid. The fatty acid or amine is presentin an amount from about one to about fifteen times the molar amount ofthe pharmaceutically active agent, preferably two to ten times the molarof amount of the pharmaceutically acceptable agent.

The formation of a salt composed of a pharmaceutically active agent anda fatty acid or amine can be accomplished by a melt process, with orwithout the use of a solvent. One or more fatty acids or amines areheated above their melting point and the pharmaceutically active agent,in free base or acid form, is added to the molten fatty acid or amineeither directly or after dissolution of the active agent in anappropriate solvent, such as methylene chloride. The lipophilic compoundis present in excess (on a molar basis) relative to the pharmaceuticallyactive agent. The lipophilic compound is present, preferably, in anamount one to fifteen times the molar amount of the pharmaceuticallyactive agent, more preferably, two to ten times the molar amount of thepharmaceutically active agent. The mass of fatty acid or amine requiredto dissolve the active agent is a function of the chain length of thefatty acid or amine. For example, oxycodone base can be dissolved in amolten mixture of stearic and plamitic acids at a ratio of 1:5, byweight, or in molten myristic acid at a ratio of 1:4, by weight. Thefactors determining the amount of fatty acid or amine required todissolve a given amount of base include but are not limited to basestrength, acid strength, steric hindrance of the portions of the acidand/or base molecule involved in salt formation, and the ability of thebase to form non-ionic interactions (i.e. hydrogen bonds), with the acidmolecules.

Other salts which may increase lipophilicity and, hence, lipidsolubility relative to the parent drug compound include, but are notlimited to, pectinate, tannate, phytate, salicylate, saccharinate,acesulfamate, gallate, and terephthalate salts.

In another embodiment, a drug is covalently modified to increase itslipophilicity. For example, a lipophilic compound can be covalentlyattached to a drug molecule via an ester or amide linkage. Such drugderivatives are cleaved in vivo, thus releasing the parent compound.

C. Drug Containing Microparticles

In preferred embodiments, drugs are formulated with a carrier materialto form microparticles. As used herein, the term “microparticle” refersto a composition comprising a drug dispersed within a carrier materialand “coated microparticle” refers to a composition comprising a drugcontaining microparticle or a drug particle coated with one or morecoating layers of material. Microparticles and coated microparticleshave a size range of 10 to 3000 microns in diameter.

Within microparticles, drug is preferably homogeneously dispersed in theform of fine particles within the carrier material. More preferably,drug is partially solubilized in molten carrier material or partiallydissolved with the carrier material in a mutual solvent during theformulation of the microparticles. Most preferably, drug is completelysolubilized in the carrier material or completely dissolved with thecarrier material in a co-solvent during the formulation of themicroparticles. This is accomplished through the selection of materialsand the manner in which they are processed.

Carrier materials appropriate for the fabrication of drug containingmicroparticles are either slowly soluble in water or insoluble in water,but capable of degrading within the GI tract by means includingenzymatic degradation, surfactant action of bile acids and mechanicalerosion. As used herein, the term “slowly soluble in water” refers tomaterials that are not dissolved in water within a period of 30 minutes.Preferred examples include fats, fatty substances, waxes, wax-likesubstances and mixtures thereof. Suitable fats and fatty substancesinclude fatty alcohols (such as lauryl, myristyl stearyl, cetyl orcetostearyl alcohol), fatty acids and derivatives, including but notlimited to fatty acid esters, fatty acid glycerides (mono-, di- andtri-glycerides), and hydrogenated fats. Specific examples include, butare not limited to castor oil, safflower oil, olive oil, canola oil,sunflower oil, vegetable oil, corn oil, hydrogenated vegetable oil,hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated oilsavailable under the trade name Sterotex®, stearic acid, cocoa butter,and stearyl alcohol. Oils and hydrogenated oils in admixture with oneanother may also be used as carrier materials. Suitable waxes andwax-like materials include natural or synthetic waxes, hydrocarbons, andnormal waxes. Specific examples of waxes include beeswax, glycowax,castor wax, carnauba wax, paraffins and candelilla wax. As used herein,a wax-like material is defined as any material which is normally solidat room temperature and has a melting point of from about 30 to 300° C.In a preferred embodiment, the carrier is beeswax, carnauba wax or amixture thereof.

In some cases, it may be desirable to alter the rate of waterpenetration into the hydrophobic drug containing microparticles. To thisend, rate-controlling (wicking) agents may be formulated along with thefats or waxes listed above. Examples of rate-controlling materialsinclude certain starch derivatives (eg, waxy maltodextrin and drum driedcorn starch), cellulose derivatives (eg, hydroxypropylmethylcellulose,hydroxypropylcellulose, methylcellulose, and carboxymethylcellulose),alginic acid, lactose and talc. Additionally, a pharmaceuticallyacceptable surfactant (for example, lecithin) may be added to facilitatethe degradation of such microparticles.

Proteins which are water insoluble, such as zein, are preferred carriermaterials for the formation of drug containing microparticles.Additionally, proteins, polysaccharides and combinations thereof whichare water soluble can be formulated with drug into microparticles andsubsequently cross-linked to form an insoluble network. For example,cyclodextrins can be complexed with individual drug molecules andsubsequently cross-linked.

Certain polymers may also be used as carrier materials in theformulation of drug containing microparticles. Suitable polymers includeethylcellulose and other natural or synthetic cellulose derivatives.Polymers which are slowly soluble and form a gel in an aqueousenvironment, such as hydroxypropyl methylcellulose or polyethylene oxidemay also be suitable as carrier materials for drug containingmicroparticles.

Encapsulation or incorporation of drug into carrier materials to producedrug containing microparticles can be achieved through knownpharmaceutical formulation techniques. To create a composition thatprotects drug from exposure upon mechanical disruption (eg, grinding,chewing, or chopping), the drug is intimately dispersed within thecarrier material. In the case of formulation in fats, waxes or wax-likematerials, the carrier material is heated above its melting temperatureand the drug is added to form a mixture comprising drug particlessuspended in the carrier material, drug dissolved in the carriermaterial, or a mixture thereof. Microparticles can be subsequentlyformulated through several methods including, but not limited to, theprocesses of congealing, extrusion, spray chilling or aqueousdispersion. In a preferred process, wax is heated above its meltingtemperature, drug is added, and the molten wax-drug mixture is congealedunder constant stirring as the mixture cools. Alternatively, the moltenwax-drug mixture can be extruded and spheronized to form pellets orbeads. For formulations comprising salts composed of a pharmaceuticallyactive agent and one or more fatty acids or amines, the one or morefatty acids or amines are melted and mixed with the free base or acidform of the active agent at a temperature above the melting point(s) ofthe fatty acid(s) or amine(s) but below the melting point of the activeagent. Once a homogeneous mixture is formed, a carrier material such asa fat, fatty substance, wax or wax-like substance can be added to themolten mixture to yield a single phase composition. The molten solutionis solidified and formulated into microparticles. Detailed descriptionsof these processes can be found in “Remington—The science and practiceof pharmacy”, 20^(th) Edition, Jennaro et. Al., (Phila, Lippencott,Williams, and Wilkens, 2000).

For some carrier materials it may be desirable to use a solventevaporation technique to produce drug containing microparticles. In thiscase drug and carrier material are co-dissolved in a mutual solvent andmicroparticles can subsequently be produced by several techniquesincluding, but not limited to, forming an emulsion in water or otherappropriate media, spray drying or by evaporating off the solvent fromthe bulk solution and milling the resulting material.

In addition to modification of the drug itself, processing conditionscan be used to influence the dispersion of the drug withinwater-insoluble or slowly water soluble material. For example, in thecase where the water in-soluble or slowly soluble material is melted anddrug is fully or partially dissolved under stirring conditions, thetemperature, agitation rate and time of processing will influence thedegree of dissolution achieved. More specifically, a more homogenousdispersion may be achieved with a higher temperature, faster stirringrate and longer processing time. Ultrasound can also be applied to themolten mixture to increase the degree of dispersion and/or the rate ofdissolution of the drug.

In some embodiments, drug in a particulate form is homogeneouslydispersed in a water-insoluble or slowly water soluble material. Tominimize the size of the drug particles within the composition, the drugpowder itself may be milled to generate fine particles prior toformulation. The process of jet milling, known in the pharmaceuticalart, can be used for this purpose. In some embodiments drug in aparticulate form is homogeneously dispersed in a wax or wax likesubstance by heating the wax or wax like substance above its meltingpoint and adding the drug particles while stirring the mixture. In thiscase a pharmaceutically acceptable surfactant may be added to themixture to facilitate the dispersion of the drug particles.

D. Coated Drug Containing Microparticles

In some embodiments, drug containing microparticles or drug particlesare encapsulated within at least one water-insoluble enzymaticallydegradable material. In some instances the substrates of digestiveenzymes are naturally water-insoluble and can be utilized in theformulation without further processing. Solid esters of fatty acids,which are hydrolyzed by lipases, can be spray coated onto microparticlesor drug particles. Zein is an example of a naturally water-insolubleprotein. It can be coated onto drug containing microparticles or drugparticles by spray coating or by wet granulation techniques. In additionto naturally water-insoluble materials, some substrates of digestiveenzymes can be treated with cross-linking procedures, resulting in theformation of non-soluble networks. Many methods of cross-linkingproteins, initiated by both chemical and physical means, have beenreported. One of the most common methods to obtain cross-linking is theuse of chemical cross-linking agents. Examples of chemical cross-linkingagents include aldehydes (gluteraldehyde and formaldehyde), epoxycompounds, carbodiimides, and genipin. In addition to thesecross-linking agents, oxidized and native sugars have been used tocross-link gelatin (Cortesi, R., et al., Biomaterials 19 (1998)1641-1649). Cross-linking can also be accomplished using enzymaticmeans; for example, transglutaminase. Finally, cross-linking can beinitiated by physical means such as thermal treatment, UV irradiationand gamma irradiation.

To produce a coating layer of cross-linked protein surrounding drugcontaining microparticles or drug particles, a water soluble protein canbe spray coated onto the microparticles and subsequently cross-linked bythe one of the methods described above. Alternatively, drug containingmicroparticles can be microencapsulated within protein bycoacervation-phase separation (for example, by the addition of salts)and subsequently cross-linked. Some suitable proteins for this purposeinclude gelatin, albumin, casein, and gluten.

Polysaccharides can also be cross-linked to form a water-insolublenetwork. For many polysaccharides, this can be accomplished by reactionwith calcium salts or multivalent cations which cross-link the mainpolymer chains. Pectin, alginate, dextran, amylose and guar gum aresubject to cross-linking in the presence of multivalent cations.Complexes between oppositely charged polysaccharides can also be formed;pectin and chitosan, for example, can be complexed via electrostaticinteractions. Insoluble coatings can be formed on particles in thisfashion. It should be noted that in many cases polysaccharides arebroken down specifically by enzymes produced by bacteria within thecolon.

In some cases a water-insoluble but enzymatically degradable coatingcomprising both a protein and a polysaccharide can be produced if thecomponents are oppositely charged polyelectrolytes. Under the propertemperature, pH, and concentrations, the two polymers can interactthrough their opposite electrical charges and form a water-insolublecomplex. If a core particle is present at the time the complex phaseseparates, it will be coated. For example, gelatin and gum arabic can becoated onto a core particle utilizing this process. Optionally, thecomplex can be made irreversibly insoluble by subsequent cross-linkinginduced by chemical or physical means.

In some embodiments it may be desirable to coat the drug containingmicroparticles with a non-enzymatically degradable coating. Suchcoatings generally release drug via diffusion through pores in thecoating.

In general, any coating procedure which provides a coating on eachparticle of drug containing microparticle without significantagglomeration of particles may be used. Coating procedures known in thepharmaceutical art including, but not limited to, fluid bed coatingprocesses, granulation and microencapsulation may be used to obtainappropriate coatings. The coating materials may be any of a large numberof natural or synthetic film-formers used singly, in admixture with eachother, and in admixture with plasticizers (for example, Durkex 500vegetable oil), pigments and other substances to alter thecharacteristics of the coating. In general, the major components of thecoating should be insoluble in, and permeable to, water. However, itmight be desirable to incorporate a water-soluble substance, such asmethyl cellulose, to alter the permeability of the coating. The coatingmaterials may be applied as a suspension in an aqueous fluid or as asolution in organic solvents. The water-permeable diffusion barrier mayconsist of ethyl cellulose, methyl cellulose and mixtures thereof. Thewater-permeable diffusion barrier may also consist of water insolublesynthetic polymers sold under the trade name Eudragit® (Rohm Pharma),such as Eudragit RS, Eudragit RL, Eudragit NE and mixtures thereof.Other examples of such coating materials can be found in the Handbook ofPharmaceutical Excipients, Ed. By A. Wade and P. J. Weller, (1994),incorporated by reference herein.

As used herein, the term water-permeable is used to indicate that thefluids of the alimentary canal will permeate or penetrate the coatingfilm with or without dissolving the film or parts of the film. Dependingon the permeability or solubility of the chosen coating (polymer orpolymer mixture) a lighter or heavier application thereof is required toobtain the desired release rate.

E. Dosage Forms

There are a number of drug compositions that meet the abuse deterrentcriteria outlined above. In one embodiment a drug is homogeneouslydispersed, in a fine particulate form, within a water-insoluble orslowly water soluble material and the mixture is formulated intomicroparticles. In another embodiment a drug is partially dissolvedwithin a water-insoluble or slowly water soluble material during themanufacturing process, for example, by mixing at a temperature above themelting point of the carrier material, and the mixture is formulatedinto microparticles. In yet another embodiment a drug is fully dissolvedwithin a water-insoluble or slowly water soluble material during themanufacturing process, for example, by mixing at a temperature above themelting point of the carrier material, and the mixture is formulatedinto microparticles. In still a further embodiment, the drug containingmicroparticles, where the drug is homogeneously dispersed in aparticulate form, or has been partially or fully dissolved within thecarrier material during the manufacturing process, are coated with oneor more coatings to form coated microparticles. In a further embodiment,drug particles are coated directly with one or more coatings to formcoated microparticles.

The microparticles, coated microparticles, or a mixture thereof areformed into a solid dosage form suitable for oral administration. Forexample, microparticles or coated microparticles can be incorporatedinto hard capsules, dispersed within a soft gelatin capsule, or combinedwith appropriate excipients and tableted by compression. Themicroparticles, coated microparticles, or a mixture thereof could alsobe further dispersed in a semisolid hydrophobic material, for example, amixture of castor oil and hydrogenated castor oil.

In some embodiments, the compositions are coated with an entericcoating. Enteric coatings known in the art are applied directly to theabuse-deterrent microparticle or coated microparticle compositions orare applied to the surface of a capsule or tablet comprising the abusedeterrent microparticle and/or coated microparticle compositions.Enteric coatings known in the art include, for example, acrylic polymersthat are commercially available under the trade name EUDRAGIT®,cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate,polyvinylacetate phthalate, shellac, hydroxypropylmethylcellulosesuccinate, cellulose acetate trimelliate or mixtures thereof.

Dosage forms can include one or more drugs. When the dosage formincludes two or more drugs they can be Scheduled drugs or can be acombination of Scheduled and non-Scheduled drugs. The drugs can beincorporated into separate microparticle compositions where theScheduled drugs are incorporated into abuse deterrent microparticlecompositions and the non-Scheduled drugs are incorporated into abusedeterrent microparticle compostions, sustained release compositionsknown in the art or immediate release compositions known in the art. Thecompositions comprising the different drugs are formulated into a singlesolid dosage form suitable for oral administration, for example, theycan be incorporated into a gelatin capsule, or combined with appropriateexcipients and compressed into a tablet form. Examples of non-scheduleddrugs that may be included in dosage forms described herein include, butare not limited to, aspirin, acetaminopben, non-steroidalanti-inflammatory drugs, cyclooxygenase II inhibitors,N-methyl-D-aspartate receptor antagonists, glycine receptor antagonists,triptans, dextromethorphan, promethazine, florinal, guaifenesin,butalbital, and caffeine.

An immediate release dose can be incorporated into the formulation inseveral ways. Immediate release microparticles can be made utilizingstandard methodologies and formulated along with abuse-deterrentmicroparticle and/or coated microparticle compositions in a suitableoral dosage form. Alternatively, a coating containing drug which isavailable for immediate release can be placed on a tablet comprisingabuse-deterrent microparticle and/or coated microparticle compositionsplus appropriate excipients. Additionally, an immediate dose of drug canbe granulated or blended with rapidly dissolving excipients andsubsequently compressed (1) as one layer of bi-layer tablets in whichthe abuse-deterrent microparticle and/or coated microparticlecompositions are compressed as the other layer, or (2) as the outerlayer of compression-coated tablets in which the abuse-deterrentmicroparticle and/or coated microparticle compositions are compressed asthe inner core, or (3) into tablets in which abuse-deterrentmicroparticle and/or coated microparticle compositions are embedded.

In some embodiments, the immediate release portion of the dosage formcomprises a lipophilic drug derivative. For example, salt derivatives orcomplexes that are insoluble at a neutral pH but dissociate, therebyreleasing the parent compound, at an acidic pH are ideal for immediaterelease within the stomach. In the case of oxycodone some salts that mayexhibit this property include, but are not limited to, the tannate,phthalate, salicylate, gallate, pectinate, phytate, saccharinate,asesulfamate and terephthalate salts. Use of salts in the immediaterelease portion of the dosage form reduces the abuse potential of theimmediate release dose if the formulation is crushed and (1) snorted or(2) dissolved in water since these salts will be poorly soluble underthese conditions. It is understood by the one of ordinary skill in theart that such salts may also be used to formulate an immediate releasedosage form without a sustained release portion.

Additional mechanisms to reduce the potential for abuse can also beincorporated during the process of formulating tablets. For example,ingredients can be added to deter chewing or snorting of the finalformulation. For example, an intensely bitter substance may deterchewing, while an intensely spicy ingredient, such as capsaicin, maydeter snorting. The addition of a colored dye, which would stain theskin and mucosal surface of the nose following snorting may also serveto reduce this practice.

Optional excipients present in the oral dosage form comprising abusedeterrent microparticles or coated microparticles include, but are notlimited to diluents, binders, lubricants, disintigrants, colorants,plasticizers and the like. Diluents, also termed “fillers,” aretypically necessary to increase the bulk of a solid dosage form so thata practical size is provided for compression of tablets. Examples ofdiluents include cellulose, dry starch, microcrystalline cellulose,dicalcium phosphate, calcium sulfate, sodium chloride confectioner'ssugar, compressible sugar, dextrates, dextrin, dextrose, sucrose,mannitol, powdered cellulose, sorbitol, and lactose. Binders are used toimpart cohesive qualities powdered materials and can include materialssuch as starch, gelatin, sugars, natural and synthetic gums,polyethylene glycol, ethylcellulose, methylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, waxes andpolyvinyl pyrrolidone. Lubricants are used to facilitate tabletmanufacture; examples of lubricants include talc, magnesium stearate,calcium stearate, hydrogenated vegetable oils stearic acid, sodiumstearyl fumarate, sodium benzoate, sodium acetate, leucine, sodiumoleate, sodium lauryl sulfate, magnesium lauryl sulfate and polyethyleneglycol. Disintegrants can be added to pharmaceutical formulations inorder to facilitate “breakup” or disintegration after administration.Materials used for this purpose include starches, clays, celluloses,aligns, gums, and cross-linked polymers. A plasticizer may be includedin coating materials to alter their mechanical properties. Examples ofplasticizers include benzyl benzoate, chlorobutanol, dibutyl sebacate,diethyl phthalate, glycerin, mineral oil, polyethylene glycol, sorbitol,triacetin, triethyl citrate, glycerol, etc. In addition to the additivesabove, coloring and flavoring agents may also be incorporated into thecomposition.

Optionally, the composition disclosed herein comprises materials whereina combination of the materials is not soluble in water, organic solvent,or any combination thereof.

EXAMPLES Example 1. Preparation and Testing of Abuse-ResistantCompositions

Compositions comprising oxycodone base, a fatty acid and a third waxcomponent were prepared at several different ratios in the followingmanner. Oxycodone base (0.2 g) and Butylated Hydroxytoluene (˜1 mg) weredissolved in methylene chloride (0.7 ml). The fatty acid(s) and wax(es)were melted together at 95° C. on a heating block until clear solutionswere obtained. The oxycodone solution was added to the molten fattyacids/waxes and mixed well. The resulting clear solutions were incubatedfor 20 minutes to remove the solvent. The mixtures were then solidifiedand re-melted at 95° C. as an informal test of stability (i.e. to checkfor base precipitation). Finally, the molten solutions were poured ontosheets of aluminum foil and rapidly cooled to form solid wafers. Notethat only formulations that did not show base precipitation were castinto wafers and subjected to further analysis.

The wafer compositions described above were crushed into particles.Sample particles were subjected to the Oral Abuse Test (see FIG. 1 forprotocol). Samples were analyzed with a UV spectrophotometer. Resultsare presented in FIG. 2.

Example 2. Oxycodone with Myristic Acid as a Lipophilic Counter-Ion

Small batches of each microparticle composition were prepared with thefollowing amounts of reagents:

Oxycodone base/Myristic acid/Beeswax (1:5:2)

Ingredient Amount (g) Oxycodone base 2.2 g Myristic acid 11 g Beeswax,NF 4.4 g BHT 0.011 g total 17.611 gOxycodone base/Myristic Acid/Carnauba wax (1:5:2)

Ingredient Amount (g) Oxycodone base 2.2 g Myristic acid 11 g Carnaubawax, NF 4.4 g BHT 0.011 g total 17.611 g

-   -   (1) Myristic acid, Oxycodone base (solid), and BHT were heated        to form a homogeneous mixture free of drug crystals. Note that        no solvent was used in this stage.    -   (2) Solid wax was added to the clear solution and allowed to        dissolve. The clear mixture was stirred for 5 minutes    -   (3) The clear solution was poured onto a sheet of aluminum foil        and allowed to cool rapidly to form solid wafers

The solid wafers produced above were crushed with a mortar and pestle(Oxycodone base Myristic Acid/Carnauba wax) or cut with a razor bladefollowed by crushing with a mortar and pestle (Oxycodone base/MyristicAcid/Beeswax). Crushing was carried out with the goal of reducing theparticle size to less than 25 mesh. For Oxycodone base/MyristicAcid/Beeswax, crushing was stopped prior to reaching this endpoint dueto the difficulty in reducing the particle size of this “gummy”material.

Example 3. Abuse Resistance and Bioavailability Screen

The microparticles comprising oxycodone base/myristic acid/wax (1:5:2 byweight ratio) described above were subjected to a battery of Abuse Testsand a Bioavailability Screen (see FIG. 1 for protocols). Samples wereanalyzed via HPLC. The results are shown in Table 1.

TABLE 1 Testing Results for Particles made from oxycodone/myristicacid/wax at a ratio of 1:5:2 OAT OAT Oil OAT OAT IVAT Bioavail WaterPre- Alcohol Result Result Screen Pre-treat treat Pre-treat Sample ID(%) (%) (%) (%) (%) (%) Oxycodone 15.2 ± 1.5 2.1 ± 0.2 107.3 ± 2.4 15.9± 1.0 12.0 ± 0.4 27.8 ± 2.3 Base/Myristic acid/carnauba (1:5:2)Oxycodone 17.7 ± 0.7 2.4 ± 0.2 101.1 ± 0.6 24.0 ± 1.3 14.6 ± 0.6 25.0 ±1.6 Base/Myristic acid/beeswax (1:5:2)

Differential Scanning Calorimetry was conducted on the samples and onoxycodone base. The results are summarized in Table 2.

TABLE 2 Summary of DSC analysis on Pre-formulations made fromoxycodone/myristic acid/wax at a ratio of 1:5:2. Peak Temps Onset ofPeaks ΔH Sample (° C.) (° C.) (J/g) Oxycodone 48.5 43.1 88.2Base/Myristic acid/beeswax (1:5:2) Oxycodone 31.5 30.3 2.0 Base/Myristic51.6 49.4 78.0 acid/carnauba (1:5:2) 73.6 71.8 23.0 Oxycodone Base 222.8220.0 116.7

No peak was observed at the melting point of oxycodone base,demonstrating that no discrete base particles were present in thecompositions.

Example 4. Preparation of Drug Containing Microparticles

Sr. Quantity/Batch No. Ingredients % (g) 1 Oxycodone 10.00 125.00 base 2Myristic acid 50.00 625.00 3 Yellow 20.00 250.00 Beeswax 4 Carnauba20.00 250.00 wax total 100.00 1250.00Procedure:

-   1. Myristic acid was melted under constant stirring while    continuously sparging with nitrogen-   2. When Step 1 temperature reaches 70° C., Oxycodone base was added    and mixing is continued until a clear molten liquid was formed.-   3. Yellow Beeswax is melted in a separate container. When it reached    70° C., it is added slowly to Step 2 molten liquid and mixed for 5    minutes.-   4. Carnauba wax is melted in a separate container. When it reached    90° C., it is added slowly to Step 3 molten liquid and mixed for 5    minutes. A uniform homogeneous mixture was formed.    The molten mixture was solidified and subsequently was milled in a    Fitzmiil in the presence of dry ice in order to obtain    microparticles less than 16 mesh. It is expected that the molten    homogeneous mixture formed in step 4 could be spray congealed as an    alternative method to form microparticles with a uniform particle    size distribution.

Example 5. Preparation of Coated Drug Containing Microparticles

Drug-containing particles formulated in a manner similar to thatdescribed in Example 3 were sieved to obtain particles from 20-40 meshin size. These particles were coated with an insoluble coatingcomprising Eudragit RS 30D in a fluidized bed apparatus.

Example 6. Preparation of Tablets for Oral Administration

Drug-containing particles formulated in a manner similar to thatdescribed in Example 3 were sieved to obtain particles from 20-40 meshin size. These particles were tableted with the addition of anappropriate amount of filler, disintegrant and lubricant.

Example 7. Preparation of Capsules for Oral Administration

The drug containing microparticles from Example 3 were loaded intogelatin capsules.

It is understood that the disclosed invention is not limited to theparticular methodology, protocols, and reagents described as these mayvary. Those skilled in the art will recognize, or be able to ascertainusing no more than routine experimentation, many equivalents to thespecific embodiments of the invention described herein. Such equivalentsare intended to be encompassed by the following claims. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only. Publications cited herein andthe material for which they are cited are specifically incorporated byreference.

We claim:
 1. An abuse-deterrent, therapeutically effectivepharmaceutical composition comprising solid microparticles, wherein themicroparticles comprise: a. a fatty acid salt of a basic active agentprone to abuse, and b. one or more carrier materials selected from thegroup consisting of waxes or wax-like substances and mixtures thereof;wherein the process of making the microparticles comprises dissolvingthe active agent in free base form in a melt comprising one or morefatty acids, thereby forming a salt between the active agent and the oneor more fatty acids, and wherein the one or more fatty acids are presentin molar excess relative to the active agent.
 2. The composition ofclaim 1, wherein the one or more fatty acids are present in an amountranging from 2 to 15 times the molar amount of active agent.
 3. Thecomposition of claim 1, wherein the one or more fatty acids are presentin an amount ranging from 2 to 10 times the molar amount of activeagent.
 4. The composition of claim 1, wherein the one or more fattyacids are present in an amount ranging from 6.9 to 15 times the molaramount of active agent.
 5. The composition of claim 1, wherein the oneor more fatty acids are present in an amount ranging from 6.9 to 10times the molar amount of active agent.
 6. The composition of claim 1,wherein the one or more fatty acids is one or more C5 to C30 monovalentfatty acids, one or more C8 to C40 divalent fatty acids, or mixturesthereof.
 7. The composition of claim 6, wherein the one or more fattyacids is one or more C5 to C30 monovalent fatty acids selected from thegroup consisting of pentanoic acid, hexanoic (caproic) acid, heptanoicacid, octanoic (caprylic) acid, nonanoic acid, decanoic (capric) acid,undecanoic acid, dodecanoic (lauric) acid, tridecanoic acid,tetradecanoic (myristic) acid, pentadecanoic acid, hexadecanoic(palmitic) acid, heptadecanoic (margaric) acid, octadecanoic (stearic)acid, nonadecanoic acid, eicosanoic (arachidic) acid, heneicosanoicacid, docosanoic (behenic) acid, tricosanoic acid, tetracosanoic(lignoceric) acid, pentacosanoic acid, hexacosanoic acid, heptacosanoicacid, octacosanoic acid, nonacosanoic acid, triacontanoic acid, linoleicacid, oleic acid, and mixtures thereof.
 8. The composition of claim 7,wherein the one or more fatty acids is myristic acid.
 9. The compositionof claim 1, wherein the one or more carrier materials are present in anamount of from 0.25 to 8 times by weight of the amount of the activeagent.
 10. The composition of claim 9, wherein the one or more carriermaterials are present in an amount of from 2 to 6 times by weight of theamount of the active agent.
 11. The composition of claim 1, wherein thecarrier material is a wax selected from the group consisting of carnaubawax, beeswax, microcrystalline wax and mixtures thereof.
 12. Thecomposition of claim 11, wherein the carrier material is a mixture ofbeeswax and carnauba wax.
 13. The composition of claim 1, wherein theactive agent is oxycodone, the one or more fatty acids is myristic acid,and the carrier material comprises beeswax and carnauba wax.
 14. Apharmaceutical dosage form comprising the composition of claim
 1. 15. Apharmaceutical dosage form comprising the composition of claim
 13. 16.The pharmaceutical dosage form of claim 14, in the form of a capsule.17. The pharmaceutical dosage form of claim 15, in the form of acapsule.
 18. The composition of claim 1, wherein the active agent isselected from the group consisting of oxycodone, hydrocodone, morphine,oxymorphone, amphetamine, and methylphenidate.
 19. The composition ofclaim 18, wherein the active agent is oxycodone.
 20. The composition ofclaim 18, wherein the active agent is hydrocodone.